Klinefelter syndrome (KS) is a genetic disorder in which the testes (the male gonads) do not produce their principle hormone, testosterone. Boys with KS are generally asymptomatic until the early teenage years, because males do not normally produce significant amounts of testosterone until the onset of puberty. In adolescence, the boy with KS may be tall and long-legged, often with gynecomastia (glandular breast enlargement) and small, firm testes. These symptoms can be subtle, however, and they may easily be missed by parents and doctors. Other common features of KS are learning disabilities and attention deficits, motor delay, and speech and language trouble—but these are highly non-specific findings. KS often remains undiagnosed until the later adult years, when men visit their doctors with concerns about decreased libido and erectile dysfunction.[i]
Virtually all men with KS are infertile. Besides failing to produce testosterone, the testes also fail to perform their other principle function: sperm production. Many men with KS are diagnosed following a standard male fertility workup, which includes an endocrine panel measuring testosterone, FSH, and LH.
FSH and LH are released by the pituitary gland, and both travel through the bloodstream to the testes, where FSH stimulates sperm production and LH stimulates production of testosterone. In normal males, the resultant testosterone in the bloodstream (along with another protein called inhibin) signals the pituitary gland that FSH and LH are working properly. In response, the pituitary reduces its secretion of FSH and LH, until testosterone levels dip below a critical set point. This feedback loop is a common phenomenon of endocrine self-regulation: In normal males, it is the testes’ way of signaling to the pituitary that they’ve gotten the message and are doing their job. Internal feedback keeps circulating levels of testosterone within a narrow normal range, ideal for sexual function and body metabolism.
In Klinefelter syndrome, FSH and LH are produced normally, but the testosterone produced in response is inadequate to perform its normal hormonal functions and to provide negative feedback to the pituitary gland. The pituitary senses low or absent testosterone in the blood, and in response it bombards the testes with FSH and LH in an attempt to raise testosterone levels—but to no avail. The seminiferous tubules of the testes—where sperm and testosterone are produced—are atrophied and non-functional in men with KS. The pituitary, dangling from brainstem (far from the testes) and ignorant of its wasted efforts, continues to produce huge amounts FSH and LH. Thus the classic hormonal assay of the adult KS patient reveals strikingly elevated FSH and LH levels, with virtually absent testosterone.
The first patient report of KS in 1942 (by Dr. Klinefelter and colleagues), was followed seventeen years later by the discovery of the syndrome’s genetic etiology. In the normal human genotype, each cell contains 46 chromosomes, including two sex chromosomes: Either XX or XY. Thus the normal female genotype is 46, XX, while the normal male is 46, XY. The classic genetic abnormality of Klinefelter is an extra X chromosome, described as a 47, XXY genotype. (Other forms exist, but they are much less common.)
The extra chromosome appears as a result of “meiotic non-disjunction:” An extra X chromosome sneaks in where it doesn’t belong during the process of cell division that produces the paternal sperm or maternal ovum. Upon fusion of sperm and egg, an XXY embryo results.
In genetic terms, the presence of a Y chromosome determines male sex. The Y chromosome includes a region called SRY—the sex-determining region—which encodes for molecular signals that initiate the development of the male gonads and subsequent testosterone production, as well as development of the male internal and external genitalia. Because they possess a Y chromosome, individuals with KS are unequivocally male in genotype. But phenotypically, the classical manifestations of male sex are askew with KS, apparently thrown out of balance by the presence of an extra X chromosome.
The role of the extra X, however, is more complicated than it appears.
The mystery for doctors and researchers lies in a subtlety of sex chromosome expression called X-inactivation. In normal cells containing more than one X chromosome (such as normal XX female cells), one X is always inactive. This inactivation occurs early in embryonic development, and it leaves only one X functioning in each cell of the body. The remaining, inactivated X is called a “Barr body,” and its genes do not contribute to the function of that cell, nor to the function of the human being.
X inactivation is known to occur in all cells containing more than one X chromosome. This is significant for KS researchers, because it applies even to the cells of XXY males. The question then remains: What makes the effective genotype of a man with KS any different than that of a normal male? After X inactivation in an XXY cell, the number of active genes remaining is 46: including one X, one Y, and one inactive X—the Barr body.
A partial answer lies in what is known about Barr bodies in normal female XX cells: Although the Barr body is called “inactive,” inactivation of the second X is not absolute.[ii] A small number of its genes remain potent. In XXY males, one or more of these remaining active genes almost undoubtedly causes of the female secondary sex characteristics, atrophied tubules, and resultant infertility, but the exact molecular mechanism remains unknown.
The specifics of the extra X activity in Klinefelter syndrome, which could hold clues to effective interventions, continue to puzzle researchers and confuse medical students. Those with the greatest stake in the answer, however, are patients with KS and their family members.
Kristopher Walters is not a real person; he is a “paper patient”—a fictionalized and typified case used to introduce medical students to the scientific and clinical principles of sex chromosome disorders, while at the same time reminding them that these conditions manifests themselves in real people who must cope with the symptoms in their daily lives.
Klinefelter syndrome is often called a typical “medical school disease,” a condition full of educational pearls for the student doctor, but one that is quite rare in the general population and unlikely to appear in general practice.
In my second year of medical school, shortly after “diagnosing” the fictional Kristopher Walters with Klinefelter syndrome, I had the opportunity to meet Amy Scott*, whose five-year-old son, Gabe, had been prenatally diagnosed with KS. Ms. Klinefelter spoke to a small group of medical students about Gabe and his condition, including the challenges of providing extra developmental and educational support while at the same time planning for his future, which will likely include testosterone injections beginning at puberty (to promote normal development of secondary sex characteristics), and freezing of his sperm around the same time (in hopes of using the sperm for reproduction later in his life).
Amy Scott was well-informed about Klinefelter syndrome. (She called it simply “XXY”— “I hate the word ‘syndrome’—it makes it sound like there’s something wrong with him.”) She knew all the latest interventions and attended annual research conferences. Nevertheless, I was surprised when she started talking about Barr bodies and their role in KS.
“What I really want them to figure out is the X inactivation thing,” she said, almost as though she were thinking out loud. “I mean, I’ve had it explained to me. I don’t understand all the details of course, but I understand that the extra X chromosome isn’t actually doing anything. It’s shut down. So what’s going on there? It’s a mystery. I wish they’d figure it out.”
I was stunned. Here was a young mother who knew everything there was to know about the science behind her son’s condition. She even knew what science couldn’t tell her. As a medical student and future doctor, I felt suddenly ashamed of the gaps in the research—the gaping black hole of X inactivation and the molecular mechanisms of KS.
This black hole has inspired abundant research and numerous scientific papers in the clinical and basic sciences. Like all medical and scientific mysteries, however, the importance of X inactivation transcends the curiosity of doctors and researchers, who love to explain everything with their neat pathways and principles. As a medical student, the case of Kristopher Walters was my first introduction to Klinefelter syndrome, and to the incredible realm of scientific mystery and unsolved problems in medicine. Amy Scott re-introduced me to the role of scientific research and discovery for patients’ and their families. For individuals with Klinefelter syndrome, the mystery of X inactivation can represent not only frustration, but sometimes also profound despair—and always potential for hope.